Impaired nitrogenous waste clearance promotes hepatocellular carcinoma.

In mammals, hepatic urea cycle enzymes (UCEs) convert ammonia, the toxic nitrogenous waste, into urea for excretion. In hepatocellular carcinoma (HCC), UCE expression is often heterogeneously repressed, but its role in tumorigenesis is unclear. We show that, as in patients, UCE expression is markedly reduced in multiple HCC mouse models, including those driven by oncogenic c-MET/β-catenin, leading to impaired ammonia clearance, altered amino acid metabolism, and increased pyrimidine synthesis. In contrast, UCE expression is largely preserved in c-MET/sgAxin1 tumors, allowing assessment of the consequences of UCE loss. Silencing individual UCEs increases ammonia burden and accelerates HCC with reprogrammed amino acid and pyrimidine metabolism, supporting a causal role for defective ammonia detoxification in oncogenesis. Notably, dietary protein restriction lowers hepatic ammonia and slows tumor growth. These findings establish a mechanistic link between nitrogen overload and hepatocarcinogenesis and highlight protein restriction as a feasible therapeutic strategy for patients with impaired nitrogenous waste handling.